3-imino-cephalosporins

ABSTRACT

3-Imino-cephalosporin derivatives of formula II ##STR1## wherein Y denotes alkyl, aryl or heterocyclyl; and R a  and R d  denote hydrogen or a silyl group; in free form or in salt form, and methods of preparation.

This application is a divisional of Ser. No. 08/732,501, filed Oct. 23,1996, now U.S. Pat. No. 5,856,474, which is a 371 of PCT/EP95/01538,filed Apr. 24, 1994.

This invention relates to new intermediates in the preparation ofcephalosporins. Particularly it relates to a compound of formula##STR2## wherein either α) R^(a) denotes hydrogen or a silyl group;R^(b) denotes a group of formula --OR^(c), wherein R^(c) denoteshydrogen or alkyl; and R^(c) and R^(d) together denote a bond; or

β) R^(a) and R^(d) denote hyrdrogen or a silyl group; and R^(b) andR^(c) together denote an imino group of formula═N-Y, wherein Y denotesalkyl, aryl or heterocyclyl; or

γ) R^(d) denotes hydrogen or a silyl group; R^(a) denotes hydrogen, ifR^(d) denotes hydrogen; or, R^(a) denotes hydrogen or a silyl group, ifR^(d) denotes a silyl group; and R^(b) and R^(c) together denote the oxogroup; in free form or in salt form.

In one particular aspect the invention relates to a compound of formula##STR3## wherein X⁻ denotes the anion of an inorganic or organic acidand R₁ denotes hydrogen or an alkyl group.

In another particular aspect the invention relates to a compound offormula ##STR4## wherein R denotes hydrogen or a silyl group.

In another particular aspect the invention relates to a compound offormula ##STR5## wherein Y and R are as defined above in free form orsalt form.

Alkyl, aryl or heterocyclyl in the meaning of Y include unsubstitutedalky, aryl or heterocyclyl; or, by amino, dialkylamino, hydroxy, alkoxy,alkyl, aryl, nitro, halogen, carbalkoxy or carbamido substituted alkyl,aryl or heterocyclyl. Y denotes preferably tert.-butyl, phenyl, naphthylor pyrimidinyl.

If not otherwise stated herein alkyl includes an alkyl group having 1 to22, for example 1 to 12, such as 1 to 8 carbon atoms, preferably loweralkyl, such as (C₁₋₄)alkyl. An alkyl group may be unsubstituted orsubstituted by groups which are inert under relevant reactionconditions. A silyl group is preferably a silyl protecting group andincludes a conventional silyl protecting group, such as a trialkylsilylgroup, for example the trimethylsilyl group. An aryl group includes arylhaving 6 to 18 carbon atoms, preferably phenyl, napthyl. An aryl groupmay be unsubstituted or substituted by groups which are inert underrelevant reaction conditions. Hetreocyclyl include heterocyclic groupsmentioned below in the meaning of R₅ and R₆. A heterocyclic group may beunsubstituted or substituted by groups which are inert under relevantreaction conditions.

A compound of formula Ia wherein R^(a) and R^(d) denote hydrogen is atautomeric aldehyde form of a compound of formula I in free base formwherein R₁ denotes hydrogen; A compound of formula II may be used as anintermediate in the production of a compound of formula I.

A compound of formula IA, particularly a compound of formula I, Ia orII, is an useful intermediate in the production of highly activeantibiotics. It may be used to prepare a wide variety of cephalosporinswhich are substituted at the nitrogen atom in position 7 and in position3 of the cephalosprin structure with a wide variety of groups which areuseful groups in respect to the activity of the correspondingcephalosporin. A compound of formula I is as such, or, in equilibriumwith its tautomeric aldehyde form of formula Ia wherein R denotes asilyl group, suitable as starting material, for example for Wittigreactions, for decarbonylation reactions, for the production of mostvaried aldehyde derivatives. At the same time one is free to formdesired derivatives in position 7, for example by acylation.

Examples of highly active antibiotics which may be obtained from thecompounds of the invention in conventional manner are ceftibuten as anexample for a decarbonylation product; cefixim, cefdinir, E-1077 or, thecompounds of EP 620 225, for example the compounds A to P of EP 620 225,as examples for Wittig products; or compounds having the structure offormula A, disclosed in EP 392 796, as a thioacetal (the thioacetalstructure of formula A may be prepared for example according to J.Antibiotics 44(4), 415-21(1991): ##STR6##

Processes for the production of a 3-formyl-cephalosporin or of acompound of formula I, which are acylated at the nitrogen atom inposition 7 are known from literature. They start exclusively from7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylic acids (esters),7-benzylidene-3-hydroxymethyl-3-cephem-4-carboxylic acids (esters),7-acylamino-3-halogenmethyl-3-cephem-4-carboxylic acid esters or from7-acylamino-3-cephalosporin lactones.

For example, according to Helvetica Chirnica Acta, vol. 57, no. 219,pages 2044ff (1974) by H. Peter and H. Bickel, a 3-formyl-cephalosporinwhich is acylated at the nitrogen atom in position 7 is produced bymeans of oxidation of the corresponding7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylic acidbenzhydrylester, and subsequently analogues of formula I (R₁ =H ormethyl) which are, however, acylated at the nitrogen atom in position 7by a phenylacetyl group are produced by cleavage with trifluoro aceticacid in the presence of ortho formic acid methyl ester. Apart from theuse of complicated protecting group technology, the process has theparticular disadvantage that the oxidation of the alcohol to thealdehyde is accompanied with undesired Δ-2 isomerisation andlactonisation. In addition, the oxidation agents used, such aschromium(VI)oxide, and cleavage reagents, such as trifluoro acetic acid,may not be used in technical scale for ecological reasons.

A process for the production of7-phenylacetylamino-3-formyl-3-cephem-4-carboxylicacid-p-methoxybenzylester, starting from the corresponding 3-iodomethylcompound, is described by H. Tanaka et al in Synlett, page 660, Nov.1990. The oxidation agent used is O₂ with rhodium chloride and aluminiumas catalyst. The oxidation product must be purified by chromatographyand the yields are a maximum of 66%.

In DE 2 360 620, a 7-acylamino-3-hydroxymethyl-3-cephem-4-carboxylate isoxidized using chromic acidisulphuric acid to give the correspondinglactone. Reference is made to stability problems with the correspondingtautomer aldehyde in respect to the lactone form of formula I. The useof chromic compounds is excluded from technical scale for ecologicalreasons.

Chem. Pharm. Bull. Vol. 28, pages 1339 ff, 1980, describes a process forthe production of 7-acylamino-3-formyl-3-cephem-4-carboxylic acidhydroxylactols, starting from the corresponding lactones, viabromination, followed by halogen-hydroxy exchange. The conditions toavoid bromination of the thiazine nucleus must be carefully chosen.

According to the present invention a compound of formula IA,particularly of formulae I, Ia, Ib and II may surprisingly be producedwithout complicated protecting group technology and without thedisadvantages of the prior art specified above. This may take place in avery simple way and results in high yields.

Accordingly, in another aspect the invention relates therefore to aprocess for the production of a compound of formula IA as defined aboveby

a) for the production of a compound of formula IA, group α),

splitting the double bond in position 3 of the ring structure of acompound of formula ##STR7## wherein R₂ and R₃ are the same or differentand independently of each other denote hydrogen or an organic group, andX⁻ is as defined in formula I, in the presence of ozone, and, ifdesired, converting a compound of formula IA, group α) wherein R^(c)denotes alkyl, thus obtained, into the corresponding free base offormula ##STR8## wherein R^(c) denotes alkyl and, if desired, convertingthe free base of formula Ib into a salt of formula IA which has adifferent salt anion than that used in the starting compound of formulaIII, or

b) for the production of a compound of formula IA, group β), treating acompound of formula ##STR9## wherein R denotes a silyl group, Z denotesP⁺ (R₄)₃ I⁻ or P(O)(OR₄)₂ and R₄ denotes lower alkyl or aryl, with atleast one strong organic base in combination with a silylation agent andreacting with a nitroso compound of formula

    Y--N═O                                                 V

wherein Y is as defined in formula IA, and, if desired, converting thefree form of formula IA thus obtained in a salt form of formula IA, or

c) for the production of a compound of formula IA, group α) which is acompound of formula ##STR10## wherein X⁻ is as defined above, treating acompound of formula ##STR11## wherein R denotes a silyl group or adesilylated form thereof of formula ##STR12## wherein Y is as definedabove, with at least one strong aqueous inorganic acid or at least onestrong organic acid, or

d) for the production of a compound of formula IA, group γ),

γα) treating a compound of formula ##STR13## with a base, resulting in acompound of formula ##STR14## wherein R denotes hydrogen, and, ifdesired, reacting a compound of formula Ia wherein R denotes hydrogen,with a silylation agent, resulting in a compound of formula Ia wherein Rdenotes a silyl group, or

γβ) reacting a compound of formula Ic with a silylation agent, resultingin a compound of formula Ia wherein R denotes a silyl group, and, ifdesired,

converting a compound obtained according to a) to d) in the free form ina salt form thereof or vice versa.

Process a) follows the following reaction scheme:

COMPOUND OF FORMULA III ##STR15##

Process a) is an ozonolysis reaction. It may be carried out in a solventor solvent mixture which contains alcohol or which is alcohol-free withor without the presence of water. Solvents which may be employed includealcohols, such as a straight chain or branched (C₁₋₄)alcohol, or organicsolvents which are inert under the reaction conditions, such ashalogenated hydrocarbons, for example dichloromethan; or esters, forexample acetic acid esters; in combination with a (C₁₋₄)alcohol; with orwithout the presence of water. For example, a compound of formula III(which may be prepared, for example, according to EP 503 453) in whichpreferably R₂ or R₃ denotes hydrogen and the corresponding R₃ or R₂denotes preferably hydrogen, alkyl, cycloalkyl, aryl, or, a group offormula

    --CH.sub.2 --A

wherein A denotes preferably hydrogen, hydroxy, alkoxy, acyloxy, halogenand X⁻ is as defined above, or,

the free base of a compound of formula III, treated in an alcohol or inan alcohol-containing solvent mixture with an inorganic or organic acid,is suspended or dissolved in an alcohol or in a solvent mixturecontaining an alcohol and a solvent which is stable in the presence ofozone, and ozonolysis is carried out in conventional manner. If desired,a reducing agent, such as a sulphide or phosphine may be added to thereaction mixture during or after ozonolysis. The compound of formula IA,group α), wherein R^(a) =H (=compound of formula I wherein R₁ is asdefined above), may be isolated, for example, by precipitating with ananti-solvent, if desired after (partial) removal of thesolvent(mixture). If ozonolysis is carried out in an alcohol-freemedium, a compound of formula I wherein R₁ denotes hydrogen may beobtained. If ozonolysis is carried out in an alcohol-containing medium,a compound of formula I wherein R₁ denotes hydrogen or a compound offormula I wherein R₁ denotes alkyl may be obtained. Ozonolysis in analcohol as solvent and work up at low temperatures may result in acompound of formula I wherein R₁ denotes hydrogen. If the reactionmixture is left at elevated temperatures, for example at roomtemperature, particularly in the presence of an excess of an acid HXwherein X denotes the anion of an inorganic or organic acid, a compoundof formula I wherein R₁ denotes alkyl may be obtained. If in thealcohol-containing solvent additionally water is present or water isadded without an addition of an excess of an acid HX, a compound offormula I wherein R₁ denotes hydrogen may be isolated. A compound offormula I wherein R₁ denotes hydrogen may be converted into a compoundof formula I wherein R₁ denotes alkyl by addition of little water or byprolonged standing in an alcohol-containing medium. Conversion of acompound of formula I wherein R₁ denotes alkyl into a compound offormula I wherein R₁ denotes hydrogen and vice versa may be effected inseparate steps as described below.

An isolated compound of formula I wherein R₁ denotes alkyl may be easilyconverted into a compound of formula I wherein R₁ denotes hydrogen asfollows: A compound of formula I wherein R₁ denotes alkyl is dissolvedor suspended in water or in an organic solvent mixed with a littlewater. Acid may be added additionally, and the compound of formula Iwherein R₁ denotes hydrogen and the corresponding alcohol are formed.The product may precipitate, or, isolation may be effected asconventional, for example by addition of an anti-solvent, optionallyafter removing the solvent and water. Suitable solvents include water incombination with at least one alcohol, nitrites, e.g. acetonitrile, orketones, for example acetone. Anti-solvents include solvents forcompleting precipitation or enhancement of yields, such as organicsolvents which are water-free, for example hydrocarbons, ketones,nitrites, ethers or esters.

Alternatively, the compound of formula I wherein R₁ denotes hydrogen maybe dissolved or suspended in an alcohol or in a solvent mixturecontaining an alcohol, optionally adding additional acid, and theproduct of formula I wherein R₁ denotes alkyl may be isolated either bysimple filtration or it may be precipitated by adding an anti-solvent,optionally after concentration. Suitable solvents include, for example,the corresponding alcohols; nitriles such as acetonitrile; esters suchas ethyl acetate; ketones, such as acetone in the presence of thecorresponding alcohol; particularly alcohols. Anti-solvents are forexample ethers or hydrocarbons. For completing precipitation thereaction mixture may be diluted with hydrocarbons, ketones, nitrites,ethers or esters. Suitable acids include for example (strong) inorganicacids such as hydrohalic acids, nitric acid or perchloric acid and(strong) organic acids, including for example organic sulphonic acidssuch as benzenesulphonic acid or toluenesulphonic acid.

Surprisingly, no isomeric sulphoxides are produced in the ozonolysisreaction, and similarly, the isolated compounds of formula I are free ofundesired Δ-2 compounds. Furthermore polymerisation of a compound offormula I, which may be regarded as aminoaldehyde derivative, isavoided.

In a compound of formula IA a new assymmetric centre is established inthe lactol ring due to its production according to the invention.Depending on the reaction conditions mixtures of both diastereoisomersor one or the other of the diastereoisomers may be obtained. Thespecific diastereoisomer form may be detected, for example, by ¹ H-NMR.The invention relates to both diastereoisomers as well as to mixturesthereof including racemic mixtures. Separation of the diastereoisomersmay be carried out in conventional manner, if desired, for example bychromatography.

A compound of formula I wherein R₁ denotes alkyl may be converted into acompound of formula Ib wherein R^(c) denotes alkyl by use of a base andthereafter reconverted in a compound of formula I, wherein X⁻ isdifferent from the original X⁻ of the compound of formula III by use ofan acid HX wherein X denotes a desired anion of an inorganic or organicacid. Suitable bases include organic amines, such as arylic amines, forexample pyridine, or aliphatic amines, for example triethylamine.Suitable solvents for the production of a compound of formula Ib includethe corresponding alcohols optionally in combination with an ester,ketone, ether or nitrile.

Process b) relates to the reaction of a compound of formula IV wherein Rdenotes a silyl group (which may be obtained, for example, by theprocess described according to EP 503 453), with a nitroso compound offormula V to give a compound of formula IA, group β) (=compound offormula II) in the form of a free base. The reaction may be carried outin the presence of at least one strong organic base in combination witha silylation agent and a solvent. A strong organic base includes, forexample, a guanidine or an amidine, such as1,8-diazybicyclo[5.4.0]-undecene-7-ene (=DBU) or1,5-diazybicyclo[4.3.0]non-5-en (=DBN); an alkali salt of a nitrogencontaining compound, such as the Li or Na salt of hexamethyldisilazaneor of an iminophosphorane; a Li salt of a carboxylic acid, such as Liacetate; or an epoxide, such as propylene-oxide or butylene-oxide;preferably propylene-oxide or butylene-oxide. Examples for a silylationagent include bistrimethylsilylacetamnide, bistrimethylsilyl urea. Thereaction is preferably carried out in a solvent which is inert under thereaction conditions. Suitable solvents include halogenated hydrocarbons,such as methylene chloride; amides, such as dimethylformamide,dimethylacetamide; ethers, such as tetrahydrofurane. In the case that anepoxide is used, it may act as a base.

About 1 to 1.5 mol, preferably about 1.2 mol of the organic base andabout 0.5 to 2 mol, preferably about 1.5 mol of the silylation agent maybe used per mol of the starting compound of formula IV.

The chemical nature of the nitroso compound is not critical. A suitablenitroso compound includes an aliphatic, aromatic or heterocyclic nitrosocompound, preferably an aromatic nitroso compound, more preferably anitrobenzene compound, such as p-nitrobenzene. The nitroso comopound maybe unsubstituted or in any position substituted, for example by halogen,nitro, alkyl, alkoxy, a nitrogen containing substituent or a functionalgroup, such as carbalkoxy or carboxamido. Equivalent amounts of thestarting compound of formula IV and of the nitroso compound of formula Vmay be used. An excess of one or the other may be useful. The processmay be carried out within a broad temperature range, for example at atemperature of between +5 and -20° C.

The silyl groups R^(a) and R^(d) in a compound of formula IA, group β),thus obtained may be removed by simple hydrolysis or alcoholysis, forexample by addition of an alcohol, for example an (C₁₋₄)alcohol to thereaction mixture after the reaction between a compound of formula IV andformula V. The desilylated imino compound of formula IIa mayprecipitate.

A compound of formula IA obtained in free form may be converted into acompound of formula IA in salt form and vice versa in conventionalmanner.

Process c) is a hydrolysis reaction and results in a compound of formulaIA, group α), wherein R^(a) denotes hydrogen in salt form, i.e. acompound of formula Ic. Hydrolysis is carried out by treating a compoundof formula II or of formula IIa with at least one strong inorganic acid,such as hydrochloric acid, hydrobromic acid, sulphuric acid, or at leastone strong organic acid, such as a sulphonic acid, for example ptoluenesulfonic acid or methan sulfonic acid in an aqueous solvent or solventmixture. Solvents for hydrolysis reactions are known. The process may becarried out either after isolation of a compound of formula II,respectively IIa, or directly in the reaction mixture wherein a compoundof formula II was prepared. A compound of formula Ic may be separatedfrom the amine which is produced in the course of the reaction, forexample by extraction of the aqueous reaction mixture with awater-immiscible solvent or by precipitation of the compound of formulaIc, for example by use of an anti-solvent which is water miscible, suchas acetone, acetonitrile or isopropanol, if desired, after concentrationby removing of at least a part of the solvent. Isolation of a compoundof formula Ic may be carried out for example by lyophilisation.

The reaction of a compound of formula IV into a compound of formula Icby means of an intermediate of formula II is new and surprising. It ispossible to produce a compound of formula I by the process according tothe invention in spite of the great tendency towards ring opening of theβ-lactam system under hydric conditions (Y. Fujisawa and T. Kanzaki, J.Antibiotics 28, 376, 377; J. E. Baldwin, R. M. Adlington, N. P. Crouchand I. A. C. Pereira, Tetrahedron vol. 49, no. 22, 4915(1993); J. E.Baldwin, K. C. Goh and C. J. Schofield, J. Antibiotics vol. 45, No. 8,1378-1380, (1992) and the very strong tendency of aminoaldehydes topolymerise due to condensation reactions (Houben Weyl, Methoden derOrganischen Chemie, 7/1, pages 156 and 403, Beilstein H 14, pages 23,28, 30; and E II, page 22).

Process d) is directed to the production of the aldehyde of formula IA,group γ) and concerns a process which influences the tautomericequilibrium between a compound of formula IA, group α) (formula Ic) anda compound of formula IA, group γ) (formula Ia). A compound of formulaIc, for example produced according to process a) or process c) may beused in the production of a compound of formula IIa. An isolatedcompound of formula Ic, or, a compound of formula Ic formed in situ inthe process of its preparation may be used. The reaction may be carriedout by addition of a base to the reaction mixture, preferably in thepresence of a solvent or solvent mixture which is inert under thereaction conditions. Suitable inert solvent include for examplealcohols, such as methanol, nitrites, such as acetonitrile, ketones,such as acetone, esters or halogenated solvents, water or a mixture ofsolvents mentioned above. Suitable bases include aliphatic or aromaticamines, the conjugated acids of which being soluble in the solvent used,for example triethylamine or pyridine. If water is used as solvent or,if water is present in the reaction mixture, an inorganic base, such asa carbonate or a hydrogen carbonate or the salt of a weak organic acid,such as sodium acetate may be used. The base may be used in anapproximately equivalent amount or in an excess, preferably in anapproximately equivalent amount in respect to a compound of formula Icused as starting material. The arninoaldehyde carboxylic acid of formulaIa wherein R denotes hydrogen formed during the reaction may beisolated, for example by filtration if it is insoluble in the reactionmedium.

A compound of formula Ia wherein R denotes a silyl group may be obtainedfrom a compound of formula Ia wherein R denotes hydrogen or from acompound of formula Ic by silylation with a silylation agent.

Silylation agents include for example N,O bis-trialkylsilylacetamnides,such as N,O-bis-trimethylsilylacetamide,N,O-bis-trimethylsilylformamide, N,O-bistrimethylsilyltrifluoracetamideand silylated ureas such as bis-trimethylsilylurea. Suitable solventsinclude solvents which are inert toward silylation agents, for examplehalogenated hydrocarbons; nitriles, such as acetonitrile; esters, forexample acetic acid ethyl ester, ethers, for example tertbutyl-methylether, tetrahydrofuran; epoxides, such as propylene oxide,butylene oxide. The amount of the silylation agent may be preferablysufficient for approximately quantitative silylation of the carboxylicacid in position 4 as well as of the amine group in position 7. It hasbeen found that thus a self-condensation of the free amine group withthe aldehyde function may be avoided. Particularly, for example, two tothree mol of silylation agent may be used per mol of the startingmaterial which is to be silylated.

The compound of formula Ia wherein R denotes hydrogen is surprisinglysufficiently stable to be isolated from aqueous solution; if desired, itmay be converted into a bissilyl compound of formula I wherein R,denotes a silyl group by addition of a silylation agent. A compound offormula I wherein R₁ denotes a silyl group is stable and may be furtherreacted in solution, if desired. Compounds of formula I and of formulaIa are thus indicated for use in the production of antibiotics, forexample by acylation at the amine group in position 7 or by reaction ofthe aldehyde group in position 3 with an aldehyde reagent Thesereactions may be carried out in conventional manner.

Suitable acylation agents include, for example, activated carboxylicacids, such as acid chlorides, mixed anhydrides or active esters.Acylation may be carried out in conventional manner. Isolation of theN-acylated compound may be carried out as conventional, for example bydesilylating with a protic solvent, for example an alcohol or water. Theacylated compound may precipitate directly, or may be precipitated withan anti-solvent or in the form of the carboxylic acid salt. It may alsobe isolated in the form of the corresponding carboxylic acid ester, forexample as benzhydrylester, by reacting the desilylated product withdiphenyldiazomethane.

The aldehyde function of the compound of formula Ia wherein R is asdefined above as well as the latent aldehyde function of its tautomericform of formula I, wherein R₁ denotes hydrogen may be reacted withaldehyde reagents. The choice between the various educts, i.e. forexample, a compound of formula Ia wherein R denotes hydrogen; or, thecompound which is in an tautomeric equilibrium with a compound offormula Ia, i.e. the compound of formula I wherein R₁ denotes hydrogen;or, a compound of formula Ia

wherein R denotes a silyl group; depends on the reaction type and thereaction conditions used in each case.

If a conventional nitrogen containing aldehyde reagent is used, such asan amine, hydroxylamine, hydrazine, guanidine or semi-carbazide, all ofthe educts of formula Ia wherein R is as defined above; or, of formula Iwherein R₁ denotes hydrogen; may be used.

If a compound of formula Ia is used wherein R₁ denotes a silyl group,both groups, i.e. the amine group in position 7 as well as thecarboxylic acid group in position 4 of the ring system should be nearlyquantitatively silylated because it was found that monosilylation at thecarboxylic acid group may result in polymerisation and decomposition.

If the aldehyde-reagent contains groups which may be silylated, thealdehyde-reagent may be conveniently employed as its silylated analogue.The reaction with the corresponding aldehyde reagent is carried out forexample in solvents mentioned above for silylation. If desired, thesolubility of the aldehyde-reagent may be increased by adding a dipolar,aprotic solvent, such as DMF or sulpholane. The reaction temperature isnot critical. The reaction may be carried out, for example, at roomtemperature or with cooling. Isolation of the reaction product may beeffected in conventional manner, for example either by desilylation witha protic solvent, such as an alcohol or water or, by extraction andsubsequent isolation from water or an organic solvent (mixture). Theproduct may precipitate.

If it is desired to react the aldehyde function of a compound of formulaI wherein R₁ denotes hydrogen, it may be reacted in a suitable solventdirectly with the desired aldehyde-reagent. If, for example, a nitrogencontaining aldehyde-reagent as defined above is used this may be used asfree compound or as a salt thereof. Suitable solvents include forexample water, polar organic solvents, such as organic amides, ketones,esters, halogenated hydrocarbons, alcohols, organic acids, such asacetic acid. Alcohols may particularly be used in mixture with water.The reaction products may precipitate or may be isolated in conventionalmanner, for example, by addition of an anti-solvent or by extractionfrom an organic solvent or solvent mixture.

If it is desired to react the aldehyde function of a compound of formulaIa wherein R denotes hydrogen, an acid may be added to the reactionmixture to enhance solubility of the compound of formula Ia and toincrease its reactivity. The reaction may be carried out in tautomericequilibrium with the compound of formula I wherein R₁ denotes hydrogenas described above.

Given the known instability of cephalosporins having an aldehyde groupin position 3, the ability of compounds of formula Ia to exist, is newand most surprising.

Some 7-acyl derivates of formula Ia, existing in the form of theirisomer hydroxylactones of formula ##STR16## wherein Ac denotes an acylgroup, are known.

Trials to convert these hydroxylactones into a salt of the isomer7-acylamino3-formyl-4-carboxylic acid of formula ##STR17## wherein Ac isas defined above and W denotes a cation, may result in decompositionunder ring opening of the labile β-lactam ring, particularly in thepresence of water.

Existence of a compound of formula Ia is, due to the very strongtendency for aminoaldehydes to polymerise due to self condensation,surprising (see Houben-Weyl; Methoden der Organischen Chemie 7/1, pages156, 403 and Beilstein H 14, pages 23, 28, 30; E II, page 22).

The compound ##STR18## is mentioned in U.S. Pat. No. 3,997,528 as partof a broad class defined by its formula II. No isolation orcharacterization is described. Existence of this compound under thecondition given for its production therein is questionable. Moreover allprevious trials to isolate the compound of formula ##STR19## having thefree aldehyde in position 3 of the ring system which corresponds tocephalosporin C and which is an envisaged biotransformation product ofCefC, failed (see for example Y. Fujisawa and T. Kanzaic, J. Antibiotics28, pages 376 to 377; J. E. Baldwin, R. M. Adlington, N. P. Crouch andI. A. C. Pereira, Tetrahedron Vol. 49, No. 22, page 4915; J. E. Baldwin,K. C. Goh und C. J. Schofield, J. Antibiotics 45, pages 1378-1380).Instead of the expected structure in all cases the ring open structureof formula ##STR20## was isolated

As already mentioned a compound of formula I or of formula Ia may beused as a starting material or as an intermediate in the production ofcephalosporins. In a further particular aspect the invention relatestherefor to the use of a compound of formula IA in the production ofceplialosporins.

In another more particular aspect the invention relates to the use of acompound of formula I as defined in claim 2 wherein R₁ denotes hydrogen;or a free form thereof of formula Ib as defined in claim 5 wherein R^(c)denotes hydrogen; or a compound of formula Ia as defined in claim 3; inthe reaction of the free or latent aldehyde function in position 3 ofthe ring system with a nitrogen containing aldehyde-reagent to give thecorresponding product.

In a further particular aspect of the invention a compound of formula Ior of formula Ia is suitable in the production of a compound of formula##STR21## wherein R₅ and R₆ are the same or different and denotehydrogen or an organic group or R₅ and R₆ denote together a substitutedor unsubstituted ring.

An organic group in the meaning of R₅ and R₆ includes, for exampleunsubstituted or substituted alkyl, aryl or heterocyclyl. Substitution,for example by halogen, alkoxy, aryloxy, a nitrogen or sulphurcontaining substituent or a functional group, such as a carbalkoxy orcarboxamido group may be in any position. R₅ and R₆ may be part of anunsubstituted or substituted ring system which may contain hetero atomssuch as nitrogen, oxygen, sulphur.

For example, one of the substituents R₅ or R₆ may denote hydrogen andthe other

a) hydrogen, lower alkyl, lower alkenyl or lower alkinyl;

b) cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl orheterocyclylalkyl; these groups may be unsubstituted or substituted bylower alkoxy, lower alkylthio, halogen, lower alkyl, nitro, hydroxy,acyloxy, carboxy, carbalkoxy, lower akylcarbonyl, lower alkylsulfonyl,lower alkoxysulfonyl, lower aminoalkylamino, acylamido one or severaltimes, for example one or three times;

c) a group of formula --CH₂ R₇, wherein R₇ denotes

α) hydroxy, lower alkoxy, formyloxy, acetyloxy, lower alkylsulfonyloxy,halogen, N-mono(oower)alkylcarbamoyloxy orN,N-di(oower)alkylcarbamoyloxy,

β) a heterocyclic group,

γ) a group of formula --S(O)_(m) R₈, wherein R₈ denotes an aliphatic,araliphatic, alicyclic, aromatic or heterocyclic group and m denotes 0,1 or 2, or

δ) an acyclic or cyclic ammonium group.

"Lower" in this context means C₁₋₆, preferably C₁₋₄.

Suitable heterocyclic groups include for example non-condensed orcondensed rings having for example 4 to 7, such as 5 or 6 ring membersin each ring. Each ring may, for example, contain up to 4 heteroatoms,such as oxygen, nitrogen or sulphur. The heterocyclic group may besubstituted, for example up to three times. Suitable substitutentsinclude for example (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen,trihalo-(C₁₋₄)alkyl, hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl,di-(C₁₋₄)alkylamino, carboxymethyl, carbamoylmethyl, sulfomethyl undmethoxycarbonylamino.

Examples for heterocyclic groups include unsubstituted and substitutedimidazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl,thiatriazolyl, oxazolyl, oxydiazolyl, benzimidazolyl, benzoxazolyl,benzothiazolyl, triazolylpyridyl, purinyl, pyridyl, pyrimidinyl,pyridazinyl, pyrazolyl und triazinyl; such as unsubstituted orsubstituted 4-hydroxy-4-pyridon-2-yl, 1,2,3-triazolyl, 1,2,4triazolyl,tetrazolyl, oxyzolyl, thiazolyl, 1,3,4-oxydiazolyl, 1,3,4-thiadiazolyl,1,2,3-thiadiazolyl; particularly 1,5-dihydroxy-4-pyridon-2-yl,5-hydroxy-1-methyl-4-pyridon-2-yl, 5-hydroxy-4-pyridon-1-yl,1-methyl-1H-tetrazol-5-yl-2-methyl-1,3,4-thiadiazol-5-yl,1-carboxymethyl-1H-teturaol-4-yl,6-hydroxy-2-methyl-5-oxo-2H-1,2,4-triazin-3-yl, 1,2,3-triazol-5-yl,4-methylthiazol-5-yl.

Examples of an acyclic amonium group include(1-carbamoyl-2-hydroxyethyl)dimethylamonium,(carbamoylmethyl)(ethyl)methylamonium, trimethylamonium.

Examples of a cyclic amonium group include pyrrolidinium, which may bemono- or disubstituted at the nitrogen atom by alkyl, carbamoylalkyl,aminoalkyl, carboxyalkyl; pyridinium or cyclopentenopyridinium, whichmay be substituted at the nitrogen atom by alkyl, halogen, hydroxy,carboxamido, alkoxycarbonyl, amino, monoalkylamino, dialkylamino.

Examples of R₅ and R₆ as part of an unsubstituted or substituted ringsystem which may contain hetero atoms such as nitrogen, oxygen, sulphurin each of the rings include for example uncondensed or condensed ringshaving 3 to 7 ring members, such as 5 or 6 ring members. The rings maybe unsubstituted or substituted, for example by (C₁₋₄)alkyl,(C₁₋₄)alkoxy, halogen, trihalo(C₁₋₄)alkyl, hydroxy, oxo, mercapto,amino, carboxyl, carbamoyl, di(C₁₋₄)alkykamino, carboxymethyl,carbamoylmethyl, sulfomethyl methoxycarbonylamino.

Processes for the preparation of compounds of formula VI are known.However, the compounds of formula VI may be prepared according to priorart only by complicated protecting group technology via several reactionsteps. For example, particularly two processes via a Wittig or a Homerreaction exist in the preparation of 3-vinylcephalosporins:

The first variant is the reaction of a compound of formula ##STR22## orof a compound of formula ##STR23## wherein R₉ denotes an acyl group or aprotecting group, R₁₀ denotes aryl, especially phenyl or lower alkyl,R₁₁ denotes a cleavable ester protecting group and Cat⁺ denotes a cationof an alkali metal or the protonated form of a strong organic base, withan aldehyde or ketone of formula ##STR24## wherein R₅ and R₆ are asdefined above, to give the corresponding 3-vinylcephalosporin.

After cleavage of R₉ and R₁₁ a compound of formula VI may be obtained.

Second variant is the reaction of a compound of formula ##STR25##wherein R₁₂ denotes an acyl group or a carbalkoxy group and R₁₁ is asdefined above with a Wittig reagent of formula ##STR26## or with a Homerreagent of formula ##STR27## wherein R₅, R₆, R₁₀ and Cat⁺ are as definedabove. After cleavage of the protecting groups a compound of formula VImay be obtained.

The second variant, the reaction of a 3-formylcephem compound lookseconomically favorable in comparison with the first variant in respectto yields, in respect to availability of the corresponding aldehyde orketone of formula IX (of the first variant), in respect to purities ofthe products or in respect to the corresponding Z/E content of theproduct, i.e. the 3-vinyl compounds obtainable by both variants.

However, according to prior art the second variant has the followingdisadvantages: J. A. Webber, J. L. Ott and R. T. Vasileff describe inJournal of Medical Chemistry vol.18, no.10, pages 986ff the reaction of7-phenyloxyacetamido-3-formyl-3-cephem-4-carboxylic acidtert.butylester-sulfoxide with phosphoranes. A sulphoxide thus obtainedhas to be reduced and purified by chromatography. Thereafter cleavage ofthe ester protecting group and cleavage of the phenoxy acetic acid hasto be carried out to convert the sulphoxide in the corresponding7-amino-3-vinyl-3-cephem-4-carboxylic acid. Further purifying steps bychromatography are necessary.

In DOS 2 103 014, experimental part B, example 1(b), the reaction of7-(2-thienyl)acetamido-3-formyl-3-cephem-4-carboxylic aciddiphenylmethylester with ethoxycarbonyltrimethylene triphenylphosphoraneto give the corresponding 3-vinylcephalosporin is described. The impureE-isomer is obtained after purification by chromatography in only 21%yield.

In EP 103 264 is disclosed to convert in a first step7-[2-(2-formamidothiazol-4-yl)2-methoximinoacetamido]-3-formyl-3-cephem-4-carboxylicacid benzhydrylester into the corresponding Δ-2-compound which is in asecond step reacted in a Wittig reaction to give the corresponding3-vinyl compound. The 3-vinyl compound has to be purified bychromatography, oxidized to give the corresponding Δ-3-sulphoxide andreduced to give the desired Δ-3-compound.

The process according to the invention avoids the deficiencies of priorart and makes the second variant economically interesting.

In another aspect the invention is therefore directed to a process forthe production of a compound of formula ##STR28## wherein R₅ and R₆ arethe same or different and denote hydrogen or an organic group or R₅ andR₆ denote together a substituted or unsubstituted ring by reaction of acompound of formula ##STR29## wherein R denotes a silyl group with acompound of formula ##STR30## or with a compound of formula ##STR31##wherein R₅ and R₆ are as defined above, R₁₀ denotes aryl or lower alkyl,and Cat⁺ denotes a cation of an alkali metal or the protonated form of astrong organic base, to give a compound of formula ##STR32## wherein R,R₅ and R₆ are as defined above and desilylating a compound of formulaXIII to give a compound of formula VI.

The Wittig or the Homer reaction may be carried out in a very simpleway. For example, N,O-bissilylilated7-amino-3-formyl-3-cephem-4-carboxylic acid as starting material isreacted with the corresponding phosphoranylidene which is added to thestarting material or the reaction is carried out in situ by addition tothe starting material of a base of formula ##STR33## wherein R₅, R₆ andR₁₀ are as defined above and Hal⁻ denotes an halogen anion, such aschlorine, bromine, iodine, to give the corresponding ylide; or the anionof the corresponding dialkoxy(diaryloxy)phosphinyl compound is added tothe starting material. After termination of the reaction the compound offormula VI may be isolated, for example in conventional manner, i.e. byhydrolysis of the silyl groups with a protic solvent such as water oralcohol or, the compound is isolated, for example, by extraction andprecipitated around the isoelectric pH.

Suitable solvents for the Wittig or Homer reaction include solventswhich are inert toward silylation agents, such as halogenatedhydrocarbons, for example methylene chloride; N,N-dialkylamides, forexample DMF; nitriles, for example acetonitrile; esters, for examplealkyl acetate, such as ethyl acetate; ethers, for exampletetrahydrofuran or methyl-tert.butyl-ether, epoxides (which may act atthat same taime also as a base), such as propylene oxid or butyleneoxid; or mixtures thereof. The reaction temperatures for Wittig orHorner reactions are not critical. The reaction may be carried out, forexample, with cooling below or around 0° C. Depending on the ylide usedlower or higher temperatures may be used.

Suitable bases for the in situ formation of the ylide from thecorresponding phosphonium salt include for example epoxides (which mayact as the same time as a solvent), such as propylene oxide; or a saltof a carboxylic acid in combination with a silylation agent. Thesilylation agent may be used to neutralize the carboxylic acid formed inthe course of the reaction as a silyl compound. Suitable silylationagents include for example N,O-bistrimethylsilylacetamide (=BSA),N,O-bistrimethylsilyltrifluoracetamide.

If a phosphonium salt, a phosphoranylene compound or a phosphinylcompound (=phosphoric compound) used contain groups which may besilylated, the phosphoric compound may be silylated before the Wittig orHomer reaction.

The stoichiometry of the aldehyde compound and the phosphoric compoundwhich may be applied depends on the basic strength of the phosphoriccompound used. The aldehyde or the phosphoric compound may be used in anexcess or both are used in approximately equimolar amounts. If ylides orphosphinyl anions having a high base strength are used the compound offormula Ia should rather be used in an excess than the ylide or thephosphinyl anion.

The compounds of formula Ia or of formula XIII have under the reactionconditions surprisingly low tendency to form Δ-2 compounds. No or almostno Δ-2 compounds may be formed if stabilized ylides are used.Additionally, Δ-2 compounds which might be formed in the course of thereaction are depleted in the course of work up.

The process according to the invention shows high trans selectivity inrespect to the double bond formed during the reaction. If, for example,a compound of formula Ia is reacted with ethoxycarbonylmethylenetriphenylphosphorane surprisingly only the trans compound is in praxiisolated. This is in contrast to results of S. C. M. Fell et al.,J.Chem. Soc. Perkin I, 1361ff, 1991 wherein the reaction of7-phenylacetamido-3-formnyl-3-cephem-4-carboxylic acid benzhydrylesterwith methoxycarbonylmethylene triphenylphosphorane results in a productcontaining about 8 to 9% of the cis isomer.

Advantages of this process according to the invention as regards priorart are simple feasibility of the reaction; simple work up; highinsensibility of the system in respect to Δ-2 isomerisation; and transselectivity in the Wittig or Homer reaction.

The following examples define the invention more specific withoutrestricting its scope. All temperatures indicated are in degree Celsiusand are uncorrected. Mixtures of isomers obtained according to theexamples may be separated, for example by chromatography.

EXAMPLE 1 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(hydroxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid) (process a)

13.8 g of 7-amino-3-[Z(/E)prop-1-en-1-yl]-3-cephem 4-carboxylicacid-hydrochloride (7-PACA) are dissolved in 200 ml of methanol and theslightly yellowish solution is cooled to -50°. At this temperature 8 lof O₂ containing ca. 2 percent by volume of ozone per minute areintroduced into this solution whilst stirring. Ozonolysis is completeafter approximately 20 minutes. HPLC indicates a practicallyquantitative and uniform reaction of the starting compound into thetitle compound. 8 l of N₂ are passed through the reaction mixture in ca.2 minutes, and the slightly cloudy solution is poured into 1400 ml ofmethyl tert.butyl ether whilst stirring. The precipitated product isfiltered under N₂, washed with a little methyl tert.butyl ether andacetonitrile, and dried in a vacuum drying chamber over a drying agent.The hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4d][1,3]thiazineis obtained in the form of a white powder with a purity (HPLC) of over95%.

¹ H-NMR (D₂ O+DCl): 3.62 (AB_(q), J=16 Hz, 2H, S--CH₂); 5.10 (2d, J=5Hz, 2H, β-lactam H); 6.20 (s, broad, 1H, O--CH--O).

EXAMPLE 2 Tosylate of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(hydroxylactone of the tosylate of7-amino-3-formyl-3-cephem-4-carboxylic acid) (process a)

12 g of 7-PACA are suspended in 200 ml of methanol, and brought intosolution by adding 9.5 g of ptoluenesulphonic acid hydrate. Thissolution is ozonised and worked up as described in example 1. Thetosylate of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineis obtained as a slightly yellowish powder.

¹ H-NMR (DMSO-d₆): 2.35 (s, 3H, CH₃); 3.7-3.9 (m, 2H, S--CH₂); 5.1-5.4(m, 2H, β-lactam H); 6.3 (d, broad, 1H, O--CH--O); 7.1 and 7.5 (A₂ B₂,J=7 Hz, 4H, Ar--H).

EXAMPLE 3 Hydrochloride of6-amino-1,4,5a,6-dihydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(methoxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid) (process a)

13.8 g of 7-PACA hydrochloride are dissolved in 250 ml of methanol,ozonised as described in example 1, and precipitated with methyltert.butyl ether. The product is filtered off, suspended in 200 ml ofacetonitrile whilst in a moist, methanol-containing state, and thesuspension is stirred for ca. 30 minutes. The precipitate which is thehydrochloride of6-amino-1,4,5a,6-dihydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineis isolated and dried in a vacuum drying chamber over phosphoruspentoxide (yellowish powder).

¹ H-NMR (DMSO d₆): 3.55 (s, 3H, O--CH₃); 3.8 (AB_(q), J=4 Hz, 2H,S--CH₂); 5.3 (2d, J=5 Hz, 2H, β-lactam H); 6.2 (s, 1H, O--CH--O).

EXAMPLE 4 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(metboxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid)(process a)

13.3 g of7-amino-3-[(Z/E)-3-acetoxy-1-prop-1-en-1-yl]-3-cephem-4-carboxylic acidare suspended in ca. 230 ml of methanol. 13.1 g of triphenylphosphineare added, and a solution is obtained after adding 10 ml ofdiisopropylether containing ca. 1 g of dry HCl, followed by a further100 ml of methanol. The solution is ozonised as in example 1, but atotal of ca. 2.4 molar equivalents of ozone are introduced over thecourse of ca. 30 minutes. After removing of an eventual residue of ozonewith N₂, the reaction mixture is discharged onto ca. 1800 ml of methyltert.butyl ether. The hydrochloride of 6-amino-1,4,5a6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineprecipitates.

The ¹ H-NMR spectrum is identical to the spectrum reproduced in example3.

EXAMPLE 5 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(methoxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid)

1 g of6-amino-4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinehydrochloride are dissolved in 5 ml of methanol. Ca. 0.5 ml ofdiisopropyl ether, which has been mixed with HCl gas, are added and themixture is stirred for ca. 10 minutes. The hydrochloride of 6-amino1,4,5a6-tetrahydro-3-methoxy-1,7dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineis precipitated by addition of ca. 50 ml of acetonitrile. Only one ofthe diastereoisomers in respect to position 3 is obtained.

¹ H-NMR (300 MHz, DMSO-d₆): 3.48(s,3H,O--CH₃); 3.73 and 3.89(AB_(q),J=18Hz,2H,S--CH₃); 5.22 and 5.32 (AB_(q),J=5 Hz, 2H,β-lactam H);6.17(s,1H,O--CH--O).

EXAMPLE 6 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-ethoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(ethoxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid)

5 g of the hydrochloride of6-amnino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineare dissolved in 30 ml ethanol. Ca. 2 ml of diisopropyl ether, which hasbeen mixed with HCl gas, are added and the mixture is stirred for ca. 10minutes. The solvent is removed in vacuo, the residue is treated withmethyl-tert.butylether and filtered off. The precipitate is a mixture ofthe diastereoisomers of the hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-ethoxy-1,7dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinein respect to position 3 of ca. 9:11.

¹ H-NMR (300 MHz, DMSO-d₆): 1.18 (2t, J=7 Hz, 3H, CH₃); 3.37 (2q, 2H,CH₂ --CH₃); 3.9 (m, 2×AB_(q), 2H, S--CH₂); 5.20 (d), resp. 5.22 (d) and5.31 (2 isochrone d) (2×ABq, J=5 Hz, 2H, β-lactam H); 6.21 and 6.31 (s,1H, O--CH--O).

EXAMPLE 7 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-propoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(propoxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid)

5 g of the hydrochloride of6amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineare dissolved in 50 ml n-propanol. Ca. 2 ml of diisopropyl ether, whichhas been mixed with HCl gas, are added and the mixture is stirred forca. 10 minutes. The solvent is removed in vacuo, the residue is treatedwith methyl-tert.butylether and filtered off. The precipitate is amixture of the diastereoisomers of the hydrochloride of6amindno-1,4,5a,6-tetrahydro-3-propoxy-1,7dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinein respect to position 3 of ca. 1:1.

¹ H-NMR (300 MHz, DMSO-d₆): 0.85 (2t, J=7 Hz, 3H, CH₃); 1.6 (m, 2H, CH₂--CH₃); 3.7 (m, 2H, O--CH₂); 4.9 (m, 2×ABq, 2H, S--CH₂); 5.20 (d), resp.5.21 (d) and 5.31 (2 isochrone d) (ABq, J=5 Hz, 2H, β-lactam H); 6.21and 6.3 (s, 1H, O--CH--O).

EXAMPLE 8 Tosylate of6-amino-1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thlazine(metboxylactone of the tosylate of7-amino-3-formyl-3-cephem-4-carboxylic acid)

15 g of the hydrochloride of6-amino-1,4,5a,6-tetrahydo-3-methoxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazineare dissolved in 30 ml methanol. 20 ml of tributylamine are added at 0°and the mixture is stirred for ca.15 minutes. The precipitate isfiltered off and washed with a little methanol (0°). The free base of6-amno-1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinethus obtained is a brown powder containing only one of the diastereomersin respect to position 3.

¹ H-NMR (300 MHz, CD₂ Cl₂): 3.51 and 3.61 (ABq, J=18 Hz, 2H, S--CH₂);3.56 (s, 3H, CH₃); 4.91 (s, broad) and 4.97 (ABq, J=5 Hz, 2H, β-lactamH); 5.82 (s, 1H, O--CH--O).

1 g of the free base obtained as described above is dissolved in 10 mlof methylenchloride and treated with a solution of 780 mg ofp-toluenesulfonic acid monohydrate in 1 ml of methanol. After 5 minutesthe solvent is removed in vacuo and the residue is treated withdiethylether and filtered. Slightly coloured crystals of one of thediastereoisomers of the tosylate of6-amino-1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineare thus obtained.

¹ H-NMR (300 MHz, DMSO-d₆): 3.48 (s, 3H, CH₃); 3.75 and 3.88 (ABq, J=18Hz, 2H, S--CH₂); 5.23 and 5.32 (ABq, J=5 Hz, 2H, β-lactam H); 6.2 (s,1H, O--CH--O); 7.1 and 7.48 (A₂ B₂, J=8 Hz, 4H, ArH).

EXAMPLE 9 7-Amino-3-(N-phenylimino)methyl-3-cephem-4-carboxylic acid(process b)

106.5 ml of bistrimethylsilyl acetamide and 412 ml of propylene oxideare added at 0° to 212.8 g of7-trimethylsilylamino-3-triphenylphosphoniummethyl-3-cephem-4-carboxylicacid-trimethylsilyl ester iodide in 460 ml of dry dimethylformamide. Thesolution is subsequently stirred at this temperature for 3 hours. 119.6g of p-nitrosobenzene are added. After stirring for 16 hours at -13°,the dark-coloured reaction solution is stirred into 2400 ml of ethanolat this temperature. The product precipitates. After stirring for 30minutes in a cooling bath, the deposit is filtered off, washed with coldethanol and dried.

¹ H-NMR (CDCl₃ +BSA): 0.09 (s, 9H, N--Si(CH₃)₃); 0.25 (s, 9H,O--Si(CH₃)₃); 1.87 (d, J=9.4 Hz, 1H, NH--Si(CH₃)₃); 4.04 (AB_(q), J=18.5Hz, 2H, S--CH₂); 4.87 (2d, J=9.4 Hz, J=5.3 Hz, 11H, β-lactam-H); 5.06(d, J=5.3 Hz, 1H, β-lactam-H); 7.14-7.41 (m, 5H, aromatics-H); 8.72 (s,1H, CH═N).

EXAMPLE 10 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(hydroxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid) (process c)

5 g of 7-amino-3-(N-phenylimino)methyl-3-cephem-4-carboxylic acid areintroduced into 150 ml of 2 N hydrochloric acid at 0°. After stirringfor 10 minutes at this temperature, the small amount of insolublestarting material is separated by filtration. The clear filtrate iswashed several times with isobutanol in order to remove aniline, and islyophilised. The hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineis thus obtained as a light bright-yellow powder.

¹ H-NMR (D₂ O+DCl): 3.77 (AB_(q), J=18 Hz, 2H, S--CH₂); 5.22 (d, J=5.2Hz, 1H, β-lactam H); 5.27 (d, J=5.2 Hz, 1H β-lactam H); 6.35 (s, broad,1H, O--CH--O).

EXAMPLE 11 Hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(hydroxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid) (processes b+c)

13.4 ml of bistrimethylsilyl acetamide and 51.5 ml of propylene oxideare added at 0° to 26.6 g of7-trimethylsilylamino-3-triphenylphosphoniummethyl-3-cephem-4-carboxylicacid-trimethylsilyl ester iodide in 50 ml ofhexamethyldisilazane-containing dichloromethane. The solution is stirredat this temperature for one hour. 7.9 g of p-nitrosobenzene are added.After stirring for 18 hours at 0°, the propylene oxide is distilled offin vacuo. The reaction mixture is stirred into 100 ml of cold 1 Nhydrochloric acid. After separation of the phases the aqueous phase iswashed several times with isobutanol to separate aniline andlyophilised. The hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineis thus obtained as a light yellowish coloured powder.

Work up the reaction mixture may also be carried out as follows: Theresidue after evaporation is stirred into 100 ml of cold 1 Nhydrochloric acid and stirred for 10 minutes at 0°. The 2-phase mixtureis filtered blank. After phase separation the product-containing aqueousphase is washed several times with isobutanol. The aqueous phase isconcentrated in vacuo and purified over an adsorber resin HP20. Thefractions containing the product are combined and lyophilised. Thehydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineis thus obtained as a white powder.

The ¹ H-NMR spectrum is identical to the spectrum of example 1.

EXAMPLE 12(6R-trans)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid (=7-amino-3-formyl-3-cephem-4-carboxylic acid)(process d)

2.64 g of the hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(hydroxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid) are dissolved in 50 ml ofmethanol. A solution of 0.78 g of pyridine in 10 ml of methanol is addeddropwise to this solution whilst stirring and cooling with ice. Theprecipitated product is filtered off under nitrogen whilst excludingmoisture, washed with a little methanol and dried over a drying agent invacuo at room temperature.(6R-trans)7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid is thus obtained in the form of a light brown powder.

IR (KBr): 1799 cm⁻¹ (β-lactam), 1672 cm⁻¹ (CHO), 1606 and 1542 cm⁻¹(carboxylate) UV spectrum: λ_(max) in H₂ O=302 nm.

EXAMPLE 13 7-trimethylsilylamino-3-formyl-3-cephem-4-carboxylic acidtrimethylsilylester (process d)

A suspension of 100 mg of6-amino-1,4,5a,6tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine(hydroxylactone of the hydrochloride of7-amino-3-formyl-3-cephem-4-carboxylic acid) in 1 ml ofdeuterochloroform is mixed at room temperature with 0.28 ml of BSA. Thereaction mixture is stirred for 10 minutes at room temperature. A clearsolution is obtained. The reaction solution has the following ¹ H-NMRspectrum:

1.40 (d, J=12 Hz, 1H, NH-[TMS]₂); 3.57 (AB_(q), J=18.3 Hz, 2H, S--CH₂);4.80 (2d, J=12 Hz, J=5.3 Hz, 1H, β-lactam-H); 4.90 (d, J=5.3 Hz, 1H,β-lactam-H); 9.81 (s, 1H, CH═O).7-trimethylsilylamino-3-formyl-3-cephem-4-carboxylic acidtrimethylsilylester may be obtained from this solution by means ofevaporation.

EXAMPLE 14: 7-trimethylsilylamino-3-formyl-3-cephem-4-carboxylic acidtrimethylsilylester

2.28 g of 7-amino3-formyl-3-cephem-4-carboxylic acid are stirred for 15minutes at 0° in a mixture of 50 ml of dichloromethane and 20 ml ofacetonitrile with 5.4 ml of N,O-bis-(trimethylsilyl)acetamide. A lightyellow solution is obtained.7-trimethylsilylamino-3-formyl-3-cephem-4-carboxylic acidtrimethylsilylester may be obtained from this solution by means ofevaporation.

EXAMPLE 15(6R-trans)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylicacid (7-amino-3-formyl-3-cephem-4-carboxylic acid) (processes a+d)

A solution of 956 g7-amino-3-[(E/Z)-prop-1-en-1-yl]-3-cephem-4-carboxylicacid-hydrochloride in 7 l methanol is ozonized as described in example1(temperature: -50°; 10 l oxygen containing ca. 4 percent by volume ofozone/minute are introduced). Ozonolysis is terminated after ca. 4hours. 40 l of N₂ are passed through the reaction mixture in ca. 5minutes. The reaction temperature is raised to -35° and 5.6 1 of anaqueous, 5% waβrigen solution of sodium acetate are added whilststirring without further cooling. The precipitate is immediatelyfiltered under nitrogen whilst excluding of moisture, washed 2 timeswith 25 l of acetonitrile and dried in a drying chamber at 30° for 5hours.(6R-trans)-7-amino-3-formyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylicacid is thus obtained as a light yellowish powder.

IR(KBr): 1799 cm⁻¹ (β-lactam), 1672 cm⁻¹ (CHO), 1606 and 1542 cm⁻¹(carboxylate) UV-spectrum: λ_(max) in H₂ O=302 nm.

Compounds of formulae I, Ia and II may be used for the production ofcephalosporins, for example for the production of

16)N-(1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)-phenylaceticacid amide

2 g of the tosylate of6-amino-1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazineare dissolved in 50 ml methylenchloride, cooled to 0° and treated with1.85 g of N,O-bis(trimethylsilyl)-acetamide. After 30 minutes 1.4 g ofphenylacetic acid chloride are added and the reaction mixture is stirredfor about 30 minutes at room temperature. 2 ml of methanol are addedfollowed by 5 minutes of stirring at room temperature and filtration.After removal of the solvent the residue is treated with 50 ml ofmethyl-tert.butylether and with 20 ml of methanol and filtered. One ofthe diastereomers ofN-(1,4,5a,6-tetrahydro-3-methoxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazin-6-yl)-phenylaceticacid amide is thus obtained in the form of a colourless powder.

¹ H-NMR (300 MHz, CD₂ Cl₂): 3.50 and 3.60 (ABq, J=18 Hz, 2H, S--CH₂);3.57 (s, 3H CH₃); 3.63 (AB, 2H, CH₂); 5.0 (d, J=5 Hz, 1H, β-lactam H);5.80 (s, 1H, O--CH--O); 5.94 (dd, J=9 Hz and 5 Hz, 1H, β-lactam H); 6.4(d broad, J=9 Hz, NH); 7.23-7.4 (m, 5H, Ar--H).

¹ H-NMR (300 MHz, DMSO-d₆): 3.40 (s, 3H, CH₃); 3.49 und 3.55 (ABq, J=13Hz, 2H, CH₂); 3.61 and 3.76 (ABq, J=18 Hz, 2H, S--CH₂); 5.11 (d, J=5 Hz,1H, β-lactam H); 5.87 (dd, J=8 Hz und 5 Hz, 1H, β-lactam H); 6.12 (s,1H, O--CH--O); 7.2-7.3 (m, 5H, Ar--H); 9.20 (d, J=8 Hz, 1H, NH).

17) 7-amino-3-(N-phenylimino)methyl-3-cephem-4-carboxylic acid

A suspension of 0.50 g of the hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinein 5 ml of chloroform is mixed at 0° with 2.3 ml of BSA and stirred for15 minutes. A clear solution is obtained. 0.35 ml of aniline are added.After stirring for 3 hours at 0°, the reaction mixture is stirred into30 ml of cold ethanol. The imino compound precipitates. After stirringfor 30 minutes in the cooling bath, the deposit is filtered off, washedwith ethanol and dried.

¹ H-NMR (CDCl₃ +BSA): 1.87 (d, J=9.4 Hz, 1H, NH--(TMS)₂ ; 4.04 (AB_(q),J=18.5 Hz, 2H, S--CH₂); 4.87 (2d, J=9.4 Hz, J=5.3 Hz, 1H, β-lactam-H);5.06 (d, J=5.3 Hz, 1H, β-lactam-H); 7.14-7.41 (m, 5H, aromatic H); 8.72(s, 1H, CH═N). IR(KBr): 1789 cm¹ (C═O, β-lactam).

18)[5aR(5aα,6β)]-1,4,5a,6-tetrahydro-3-hydroxy-6-phenylacetamido-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dione(=hydroxylactoneof 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid)

2.85 ml of N,O-bis-(trimethylsilyl)acetamide are added at 0° to asuspension of 1.39 g of 6-amino1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinein a mixture of 50 ml of dichloromethane and 10 ml of acetonitrile.After stirring for 10 minutes, a clear solution is obtained, into which0.6 ml of phenylacetic acid chloride are added dropwise. The reactionmixture is stirred for 30 minutes at 0° and 0.2 ml of water are added.After separating the precipitated acetamnide-HCl, evaporation iseffected in vacuo. The residue is treated with methyl-tert.butyl etherand dried.[5aR(5aα,6β)]-1,4,5a,6-tetrahydro-3-hydroxy-6-phenylacetamido-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine-1,7(4H)-dioneis thus obtained in the form of a light yellow powder.

¹ H-NMR (60 MHz, d₆ -DMSO): 3.5 (s, 2H, --CH₂ --CO); 3.75 (s, broad, 2H,SCH₂); 5.1 (d, J=5 Hz, 1H); 5.9 (dd, J=5 and 8 Hz, 1H); 6.25 (d, J=6 Hz,1H, O--CH--O); 7.25-7.3 (s, broad, 5H, Ar--H); 9.2 (d, J=7 Hz, 1H, NH).

19) Sodium salt of 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid

2.28 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid are stirred for 15minutes at 0° in a mixture of 50 ml of dichloromethane and 20 ml ofacetonitrile with 5.4 ml of N,O-bis-(trimethylsilyl)acetamide. 1.32 mlof phenylacetic acid chloride are added dropwise to the light yellowsolution obtained. The reaction mixture is stirred for 30 minutes at 0°,and is then hydrolysed with 0.4 ml of water. The cloudy brown solutionis filtered until clear, and the dichloromethane removed in vacuo. Theresidue is diluted with 20 ml of acetonitrile and then mixed whilststirring with 1.7 g of sodium-2-ethylhexanoate. Stirring continues for10 minutes at room temperature, and the precipitated product isfiltered. After drying in a vacuum, the sodium salt of7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid is thus obtained.

¹ H-NMR (60 MHz, d₆ -DMSO): 3.45 (AB_(q), J=15 Hz, 2H, SCH₂); 3.60 (s,2H, --CH₂ --CO); 5.1 (d, J=5 Hz, 1H); 5.65 (dd, J=5 and 8 Hz, 1H);7.2-7.5 (s, broad, 5H, Ar--H); 9.2 (d, J=7 Hz, 1H, NH); 9.7 (s, 1H,CH═O).

20) 7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acidbenzhydrylester

2.28 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid are bisilylated asdescribed in example 19 with 5.4 ml ofN,O-bis-(trimethylsilyl)-acetamide, reacted with phenylacetic acidchloride, and then hydrolysed with 0.4 ml of water. The hydrolysedreaction mixture is treated with 1 g of activated charcoal and thenfiltered. The yellow filtrate is mixed with 20 ml of a 10% solution ofdiphenyldiazomethane in dichloromethane, and then concentrated to 10 mlin vacuo. The product is precipitated from the residue of evaporationthus obtained by adding 100 ml of n-hexane.7-phenylacetamido-3-formyl-3-cephem-4-carboxylic acid benzhydrylester isthus obtained as a slightly yellowish product.

¹ H-NMR (60 MHz, d₆ -DMSO): 3.15 and 3.90 (AB_(q), J=18 Hz, 2H, SCH₂);3.55 (s, 2H, --CH₂ --CO); 4.9 (d, J=5 Hz, 1H, H-6); 5.90 (dd, J=5 and 8Hz, 1H, H-7); 6.6 (d, J=8 Hz, 1H, NH); 7.0 (s, 1H, CHPh₂ ; 7.25 and 7.30(2s, 15H, Ar--H); 9.62 (s, 1H, CH═O).

21) 7-Amino-3-[[(aminocarbonyl)hydrazono]methyl]-3-cephem-4-carboxylicacid

1.3 g of semicarbazide-hydrochloride are dissolved in 30 ml of water andthe solution is cooled to 0°. To this solution are added 3.0 g of thehydrochloride of6-amino-1,4,5a,6-tetrahydro3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinein small portions. The reaction mixture is stirred at 3 to 5° for 4hours. The precipitate which is7-Amino-3-[[(aminocarbonyl)hydrazono]methyl]-3-cephem-4-carboxylic acidis filtered off and washed with 10 ml of acetone.

¹ H-NMR (300 MHz, CD₃ OD): 8.35 (s, 1H, CH═N); 5.31 (d, J=5.1 Hz, 1H,CH); 5.14 (d, J=5.1 Hz, 1H, CH); 4.28 und 3.84 (ABq, J=17.9 Hz, S--CH₂).

22) 7-Amino-3-(methoxyimino)methyl-3-cephem-4-carboxylic acid

A solution of 0.25 g of O-methylhydroxylamine-hydrochloride in 7 ml ofwater is mixed at 0° with 0.79 g of the hydrochloride of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazine.After stirring for 15 hours at 0°, the suspension obtained is filtered.The crystal cake is washed with cold water and acetone. After drying invacuo, 7-amino-3-(methoxyimino)methyl-3-cephem-4-carboxylic acid isobtained as an almost white, crystalline powder.

¹ H-NMR (CD₃ COOD+CF₃ COOD): 3.99 (2H, S--CH₂): 4.01 (s, 3H, CH₃ 0);5.39 (β-lactam-H); 8.67 (s, 1H, CH═N). IR (KBr): 1799 cm¹ (C═O,β-lactam).

23) 7-Amino-3[(E)-2-tert.butoxycarbonyl]ethenyl-3-cephem-4-carboxylicacid

A suspension of 1 g of6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-aceto[2,1-b]furo[3,4-d][1,3]thiazinein 10 ml of methylenchloride is treated at room temperature with 3.6 mlBSA. The reaction mixture is stirred for 10 minutes at room temperature.A clear solution is obtained containingN,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated with 0.37 g of lithium acetate and1.5 ml of DMF. After 15 minutes whilst stirring under cooling in an icebath 1.42 g tert.butoxycarbonylmethylene-triphenylphosphorane are adde .After 24 hours stirring at 0° the reaction mixture is stirred into 30 mlof methanol. The product crystallizes. After 30 minutes stirring at roomtemperature the crystal suspension is filtered and the filter cake iswashed with methanol. After drying 0.76 g (65.4%) of7-amino-3[(E)-2-tert.butoxycarbonyl]ethenyl-3-cephem-4-carboxylic acidas a light coloured, crystalline powder are obtained.

IR-spectrum (KBr): 1803 cm⁻¹ (C═O β-lactam), 1705 cm⁻¹ (C═O ester); ¹H-NMR-spectrum (90 MHz, D₂ O+K₂ CO₃): 1.50 (s, 9H, C(CH₃)₃); 3.61 (2H,S--CH₂); 4.82 (d, J=4.5 Hz, 1H, β-lactam-H); 5.31 (d, J=4.5 Hz, 1H,β-lactam-H); 5.97 (d, J=15.0 Hz, 1H, C═CH--CO); 7.65 (d, J=15.0 Hz, 1H,CH═C--O).

24) 7-Amino-3[(E)-2-ethoxycarbonyl]ethenyl-3-cephem-4-carboxylic acid

A suspension of 1 g of 7-amino-3-formyl-3-cephem-1-carboxylic acid in 10ml of propylene oxide is treated at room temperature with 4.7 ml of BSA.The reaction mixture is stirred at room temperature for 10 minutes. Aclear solution is obtained containingN,O-bistimethylsilyi-7-an-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated with 1.45 g ofethoxycarbonylmethyltriphenylphosphonium chloride. After 44 hoursstirring at 0° the reaction mixture is worked up as described in example23). After drying 0.90 g (71.7%) of7-amino-3[(E)-2-ethoxycarbonyl]ethenyl-3-cephem-4-carboxylic acid as alight coloured, crystalline powder are obtained.

IR-spectrum (KBr): 1801 cm⁻¹ (C═O β-lactam), 1709 cm⁻¹ (C═O ester);UV-spectrum (H₂ O): λ_(max) =316.1 nm; ¹ H-NMR-spectrum (90 MHz, DMSO-d₂+CF₃ COOD): 2.24 (t, J=7.0 Hz, 3H, CH₃); 3.90 (AB_(q) J=18.0 Hz, 2H,S--CH₂); 4.18 (q, J=7.0 Hz, 2H, O--CH₂ --); 5.30 (d, J=5.0 Hz, 1H,β-lactam-H); 5.36 (d, J=5.0 Hz, 1H, β-lactam-H); 6.30 (d, J=16.0 Hz, 1H,C═CH--CO); 7.80 (d, J=16.0 Hz, 1H, CH═C--CO).

25) 7-Amino-3[(E)-2-ethoxycarbonyl]ethenyl-3-cephem-4-carboxylic acid

A suspension of 1 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in 10ml of propylene oxide is treated at room temperature with 4.7 ml of BSA.The reaction mixture is stirred at room temperature for 10 minutes. Aclear solution is obtained containingN,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated with 1.32 g ofethoxycarbonylmethyltriphenylphosphorane. After 24 hours stirring at 0°the reaction mixture is worked up as described in example 23).

IR-spectrum (KBr): 1803 cm⁻¹ (C═O β-lactam), 1736 cm⁻¹ (C═O ester);UV-spectrum (H₂ O): λ_(max) =316.1 nm; ¹ H-NMR, UV and IR spectra areidentical with the spectra of example 23).

26) 7-Amino-3[(E)-2-ethoxycarbonyl]ethenyl-3-cephem-4-carboxylic acid

A suspension of 200 mg of 7-amino-3-formyl-3-cephem-4-carboxylic acid in2 ml of THF is treated at room temperature with 1.08 ml of BSA. Thereaction mixture is stirred at room temperature for 10 minutes. A clearsolution is obtained containingN,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated dropwise with a mixture of 197 mgof diethylethoxycarbonylmethylphosphonate and 98 mg of potassiumtert.butylate in 2 ml of TBF. After 18 hours stirring at 0° the reactionmixture is worked up as described in example 23). 39 mg (15.5%) of7-amino-3[(E)-2-ethoxycarbonyl]ethenyl-3-cephem-4-carboxylic acid as abrown coloured powder are thus obtained.

¹ H-NMR, UV and IR spectra are identical with the spectra of example23).

27) 7-Amino-3[(E)-2-N-diethylcarbamoyl]ethenyl-3-cephem-4-carboxylicacid

A suspension of 300 mg of 7-amino-3-formyl-3-cephem-4-carboxylic acid in3 ml of propylene oxide is treated at room temperature with 1.4 ml ofBSA. The reaction mixture is stirred at room temperature for 10 minutes.A clear solution is obtained containingN,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated with 377 mg ofN,N-diethylcarbamoylmethylenphosphorane. After 24 hours stirring at 0°the reaction mixture is worked up as described in example 23). 205 mg(49.8%) of7-amino-3[(E)-2-N-diethylcarbamoyl]ethenyl-3-cephem-4-carboxylic acid aslight yellowish coloured powder are thus obtained.

IR-spectrum (KBr): 1798 cm⁻¹ (C═O β-lactam), 1635 cm⁻¹ (C═O amide);UV-spectrum (H₂ O): λ_(max) =315.7 nm; ¹ H-NMR-spectrum (90 MHz, DMSO-d₆d+CF₃ COOD): 1.03-1.33 (m, 6H, 2×CH₃); 3.60-3.66 (m, 4H, 2×N--CH₂ --);3.87 (AB_(q), 2H, S--CH₂ --); 5.10 (d, J=4.8 Hz, 1H, β-lactam-H); 5.31(d, J=4.8 Hz, 1H, β-lactamn-H); 6.67 (d, J=15.0 Hz, 1H, C═CH--CO); 7.88(d, J=15.0 Hz, 1H, CH═C--CO).

28) 7-Amino-3-(2-phenyl)ethenyl-3-cephem-4-carboxylic acid

A suspension of 0.3 g of 7-amino-3-formyl-3-cephem-4-carboxylic acid in3 ml of THF is treated at room temperature with 1.4 ml of BSA. Thereaction mixture is stirred at room temperature for 10 minutes . A clearsolution is obtained containing N,O-bistrimethylsilyle7-amino-3-formyl-3-cephem-4-carboxylic acid. The solution is cooled to0° and treated with a solution of 0.53 g of phenylmethylenetriphenylphosphorane in 4 ml of THF. After 24 hours stirring at 0° thereaction mixture is worked up as described in example 23). A mixture ofthe isomers (6 parts Z-isomer and 11 parts E-isomer) is obtained.

29){6R-[3(E)α,7β(Z)]}-7-{[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino}-3-(3-ethoxy-3-oxo-1-propenyl)-8-oxo-5-thia-1-azabicyclo[3.2.0]oct-2-ene-4-carboxylic acid(=7-[(2-amino-4-thiazolyl)(methoxyimino)actyl]amino-3-(3-ethoxy-3-oxo-1-propenyl)-3-cephem-4-carboxylicacid)

0.34 g of triethylamine are added dropwise at 0° to a suspension of 0.5g of 7-amino-3-[(E)-3-ethoxy-3-oxo-1-propenyl)-3-cephem-4-carboxylicacid and 0.67 g of (2-amino-4-thiazolyl)(methoxyimino)acetic acidmercaptobenzthiazolyl ester in 5 ml ethanol. The reaction mixture isstirred for 5 hours at this temperature. A clear solution is obtained.The pH is adjusted to about 2.5 by dropwise addition of dilutedhydrochloric acid. A precipitate is formed. After 1 hour stirring at 0°the crystal suspension is filtered and the filter cake is washed withethanol. After drying 0.27 g (33.6%) of7-[(2-amino-4-thiazolyl)(methoxyimino)actyl]amino-3-(3-ethoxy-3-oxo-1-propenyl)-3-cephem-4-carboxylicacid as a light coloured, crystalline powder are obtained.

¹ H-NMR spectrum (90 MHz, DMSO-d₆): 1.22 (d, J=7.0 Hz, 3H,--CH₃); 3.80(AB_(q), J=18 Hz, 2H, S--CH₂); 3.87 (s, 3H, O--CH₃); 4.18 (q, J=7.0 Hz,2H, O--CH₂); 5.25 (d, J=4.8 Hz, 1H, β-lactam H); 5.86 (dd, J=8.5 Hz;J=4.8 Hz, 1H, β-lactam H); 6.24 (d, J=16.0 Hz, 1H, C═CH--CO); 7.73 (d,J=16.0 Hz, 1H, CH═C--CO); 9.70 (d, J=8.5 Hz, 1H).

30)7-Amino-3[(E)-N-(2,2,2-trifluorethyl)pyrrolidine-2-on-3-yldenmethyl]-3-cephem-4-carboxylicacid

A suspension of 126 mg of 7-amino-3-formyl-3-cephem-4-carboxylic acid in2 ml of propylene oxide is treated at room temperature with 572 mg ofBSA. The reaction mixture is stirred at room temperature for 10 minutes.A clear solution is obtained containingN,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated with 152 mg ofN-(2,2,2-trifluorethyl)-pyrrolidine-2-on-3-yl-triphenylphosphonium-bromide.After 24 hours stirring at 0° the reaction mixture is worked up asdescribed in example 23). After drying 119 mg (57%) of7-amino-3[(E)-N-(2,2,2-trifluormethyl)pyrrolidine-2-on-3-ylidenmethyl]-3-cephem-4-carboxylicacid as a light coloured, crystalline powder are thus obtained.

IR-spectrum (KBr): 1791 cm⁻¹ (C═O β-Lactam), 1692 cm⁻¹ (C═O Amid);UV-spectrum (H₂ O): λ_(max) =324.3 nm; ¹ H-NMR-spectrum (90 MHz, DMSO-d₂+CF₃ COOD): 2.91-3.23 (m, 2H, C--CH₂ --C-pyrrolidinon); 3.47-3.58 (m,2H, N--CH₂ -pyrrolidinon); 3.99 (q, J=15 Hz, 2H, S--CH₂ --); 4.17(AB_(q), J=15 Hz, N--CH₂ -CF₃); 5.25 (d, J=3.0 Hz, 1H, β-lactam-H); 5.32(d, J=3.0 Hz, 1H, β-lactam-H); 7.47 (t, J=3 Hz, 1H, CH═C).

31)7-Amino-3[(E)-N-methylpyrrolidine-2-on-3-ylidenmethyl]-3-cephem-4-carboxylicacid

A suspension of 300 mg of 7-amino-3-formyl-3-cephem-4-carboxylic acid in3 ml of propylene oxide is treated at room temperature with 1.6 ml ofBSA. The reaction mixture is stirred at room temperature for 10 minutes.A clear solution is obtained containingN,O-bistrimethylsilyl-7-amino-3-formyl-3-cephem-4-carboxylic acid. Thesolution is cooled to 0° and treated with 445 mg ofN-methylpyrrolidine-2-on-3-yl-methylene triphenylphosphorane. After 15hours stirring at 0° the reaction mixture is worked up as described inexample 23). After drying 328 mg (83.9%) of7-amino-3[(E)-N-methylpyrrolidine-2-on-3-ylidenmethyl]-3-cephem-4-carboxylicacid as a light coloured powder are thus obtained.

IR-spectrum (KBr): 1783 cm⁻¹ (C═O β-lactam). ¹ H-NMR-spectrum (90 MHz,DMSO-d₆ +CF₃ COOD): 2.88 (s, 3H, N--CH₃); 2.80-3.56 (m, 4H,H-pyrrolidinon); 3.95 (AB_(q), J=19.3 Hz, 2H, S--CH₂); 5.21 (d, J=5.7Hz, 1H, β-lactam-H); 5.29 (d, J=5.7 Hz, 1H, β-lactam-H); 7.32 (t, J=3Hz, 1H, CH═C).

We claim:
 1. A compound of formula II ##STR34## wherein Y denotes alkyl,aryl or heterocyclyl; andR^(a) and R^(d) denote hydrogen or a silylgroup; in free form or in salt form.
 2. A compound of claim 1 wherein Ydenotes alkyl, aryl, or heterocyclyl, which alkyl, aryl or heterocyclylgroup is unsubstituted or substituted by amino-, dialkylamino-,hydroxy-, alkoxy-, alkyl-, nitro-, halogen-, carbalkoxy- or carbamido;and R^(a) and R^(d) denote a silyl protecting group or hydrogen.
 3. Acompound of claim 1 wherein Y denotes (C₁₋₂₂)alkyl or (C₆₋₁₈)aryl, whichare unsubstituted or substituted by amino, di(C₁₋₄)alkylamino, hydroxy,(C₁₋₄)alkoxy, (C₁₋₄)alkyl, nitro, halogen, carbalkoxy or carbamido; or Yis a condensed or non-condensed heterocyclyl having one or more ringswith 4 to 7 ring members in each ring, each ring containing up to 4heteroatoms, the heteroatoms being selected from the group consisting ofoxygen, nitrogen and sulphur; which heterocyclyl is unsubstituted orsubstituted by (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, trihalo-(C₁₋₄)alkyl,hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C₁₋₄)alkylamino,carboxy-methyl, carbamoylmethyl, sulfomethyl or methoxycarbonylamino. 4.7-amino-3-(N-phenylimino)methyl-3-cephem-4-carboxylic acid in free formor in salt form.
 5. A process for preparing a cephalosporin compound,which comprises preparing an intermediate of formula II ##STR35##wherein Y denotes alkyl, aryl or heterocyclyl; andR^(a) and R^(d) denotehydrogen or a silyl group; in free form or in salt form.
 6. A process ofclaim 5 which comprises acylating the nitrogen attached to the ringsystem of formula II at the 7 position.
 7. A process of claim 5 whereinY denotes a alkyl, aryl, or heterocyclyl, which alkyl, aryl, orheterocyclic group is unsubstituted or substituted by amino-,dialkylamino-, hydroxy-, alkoxy-, alkyl-, nitro-, halogen-, carbalkoxy-or carbamido, and R^(a) and R^(d) denotes a silyl protecting group orhydrogen.
 8. A process of claim 7 which comprises acylating the nitrogenattached to the ring system of formula II at the 7 position.
 9. Aprocess of claim 5 wherein Y denotes (C1-22)alkyl or (C₆₋₁₈)aryl, whichare unsubstituted or substituted by amino, di(C₁₋₄)alkylamino, hydroxy,(C₁₋₄)alkoxy, (C₁₋₄)alkyl, nitro, halogen, carbalkoxy or carbamido; or Yis a condensed or non-condensed heterocyclyl having one or more ringswith 4 to 7 ring members in each ring, each ring containing up to 4heteroatoms, the heteroatoms being selected from the group consisting ofoxygen, nitrogen and sulphur; which heterocyclyl is unsubstituted orsubstituted by (C₁₋₄)alkyl, (C₁₋₄)alkoxy, halogen, trihalo-(C₁₋₄)alkyl,hydroxy, oxo, mercapto, amino, carboxyl, carbamoyl, di-(C₁₋₄)alkylamino,carboxy-methyl, carbamoylmethyl, sulfomethyl or methoxycarbonylamino.10. A process of claim 9 which comprises acylating the nitrogen attachedto the ring system of formula II at the 7 position.
 11. A process ofclaim 5 wherein the intermediate of formula II is7-amino-3-(N-phenylimino)methyl-3-cephem-4-carboxylic acid in free formor in salt form.
 12. A process of claim 11 which comprises acylating thenitrogen attached to the ring system at the 7 position.